Early High-Dose Caffeine Increases Seizure Burden in Extremely Preterm Neonates: A Preliminary Study

Abstract

Background: Although evidence suggests that methylxanthines may lower the seizure threshold, the effect of high-dose caffeine on seizure burden in preterm infants is not known. This study reports a secondary post hoc analysis of a randomized controlled trial of early high-dose caffeine citrate therapy in preterm infants, evaluating the effect of caffeine on the seizure burden using amplitude-integrated electroencephalography (aEEG). Methods: Seventy-four preterm infants (≤30 weeks gestation) were randomized to receive high-dose (n = 37, 80 mg/kg over 36 hours) or standard-dose (n = 37, 30 mg/kg over 36 hours) caffeine citrate over the first 36 hours followed by standard maintenance therapy. Simultaneous recording of two-channel amplitude-integrated EEG was conducted over the first 72 hours of life. The primary outcome of this post hoc analysis was cumulative seizure burden over the first 72 hours of life, measured in seconds. Results: Fifteen infants were excluded due to short recordings (≤5 hours) or corrupted data files (n = 7 standard dose; n = 8 high dose). The high-dose caffeine group displayed a trend toward an increased incidence of seizures (40% vs. 58%; p = 0.1) and a threefold increase in seizure duration (48.9 vs. 170.9 seconds; p = 0.1). Conclusion: Early high-dose caffeine therapy was associated with a trend toward an increase in seizure incidence and burden. Future studies of alternative caffeine dosing regimens should include continuous EEG monitoring.

Keywords: EEG; premature infant; seizures.

FIG. 1.

CONSORT diagram depicting sample size at each stage of the study. aEEG, amplitude-integrated electroencephalography; BPD, bronchopulmonary dysplasia; CONSORT, Consolidated Standards of Reporting Trials; HFOV, high frequency oscillatory ventilation; MRI, magnetic resonance imaging; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity.